In 1989 a possible paramyxovirus etiology for giant cell hepatitis was proposed, based on electron micrographic changes seen in the livers of patients with this disease. Collaborative studies, including attempts to transmit the disease to primates, are in progress. Patients with thalassemia in Sardinia, Italy, receive monthly blood transfusions as therapy. Many of these patients have developed chronic hepatitis. Most cases could be identified as hepatitis B or hepatitis C, but some lacked markers of either of these viruses. These patients are being studied for evidence of previously unrecognized hepatitis viruses. Similarly, clinical samples from patients with acute or chronic non-A,B,C,D,E hepatitis in the United States are to be studied for biological, serological or molecular evidence of transmissible agents. Patients with fulminant non-A, non-B hepatitis generally do not have evidence of infection with any recognized hepatitis virus. Only about 10% can be identified as having fulminant hepatitis C. The remaining 90% remain a diagnostic enigma and may be infected with one or more previously unrecognized viruses. In collaborative studies, we are attempting to transmit the disease to primates. Evidence for the existence of an additional water-borne hepatitis virus has come from seroepidemiologic studies of enterically transmitted non-A, non-B hepatitis in India. From 50-100% of hepatitis cases in 16 epidemics of water-borne hepatitis were caused by HEV but 1 water-borne epidemic was caused by neither HAV nor HEV. A hepatitis virus was reported some years ago to be transmissible from a non-A, non-B hepatitis patient to marmoset monkeys. The agent, called the GB agent, could be serially transmitted in marmosets and was partially characterized. However, serologic tests could not be developed and the true origin of the virus was never satisfactorily determined. Previous studies in this laboratory with the GB agent are being reactivated and, in collaborative studies, cloning of the viral genome is being attempted. The objectives of this project are to identify and characterize new etiologic agents of hepatitis and to develop useful assays for diagnosis of infection and seroepidemiologic studies. A longer term objective is the development of passive and active immunoprophylaxis for these important human pathogens.